Recently some 1-piperazino-3-phenylindanes have been described as having neuroleptic activity (see European Patent Application No. 81300785.3).
The terms "lower alkyl" and "lower alkoxy" mean alkyl or alkoxy having from one to four carbon atoms inclusive, straight or branched, among which may be mentioned methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, methoxy, ethoxy, iso-propoxy or n-butoxy.
This invention also includes pharmaceutically acceptable salts of the compounds of Formula I formed with non-toxic organic acids. Such salts are easily prepared by methods known to the art. The base is reacted with either the calculated amount of organic or inorganic acid in a aqueous miscible solvent, such as acetone or ethanol, with isolation of the salt by concentration and cooling or an excess of the acid in aqueous immiscible solvent, such as ethyl ether or chloroform, with the desired salt separating directly.
Exemplary of such organic salts are those with maleic, fumaric, benzoic, ascorbic, embonic, succinic, oxalic, bis-methylene-salicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-amino-benzoic, glutamic, benzene sulfonic and theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromo-theophylline.
Exemplary of such inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids. Of course, these salts may also be prepared by the classical method of double decomposition of appropriate salts, which is wellknown to the art. The compounds of Formula I as well as the pharmaceutically acceptable acid addition salts thereof may be administered both orally and parenterally, for example in the form of tablets, capsules, powders, syrups or solutions for injection.
Of the phenyl-indenes of Formula I those wherein R.sup.1 is fluorine, CF.sub.3, chlorine or methyl in the 6-position, R.sup.2 is fluorine in the 4'-position, and R.sup.3 is methyl, 2-hydroxyethyl or ##STR3## wherein Z' is NH or O, have the most prominent antipsychotic activity.
According to the method of the invention the compounds of Formula I are prepared by
(a) dehydrating a compound of the formula: ##STR4## wherein R.sup.1, R.sup.2 and R.sup.3 are as defined above, X and Y are hydrogen or hydroxy, X being hydroxy when Y is hydrogen and vice versa, or
(b) treating a compound of the formula: ##STR5## wherein R.sup.1, R.sup.2 and R.sup.3 are as defined above with an acid or base, or by heating to cause migration of the double bonds in order to obtain a compound of Formula I of the formula: ##STR6## wherein R.sup.1, R.sup.2 and R.sup.3 are as defined above, or
(c) heating an acid addition salt of a compound of the formula: ##STR7## wherein R.sup.2 and R.sup.3 are as defined above and R.sup.1' is lower alkyl, lower alkoxy, hydroxymethyl, alkoxymethyl or lower alkylthio, to cause migration of one double bond to a compound of Formula I of the formula: ##STR8## wherein R.sup.1', R.sup.2 and R.sup.3 are as defined above or
(d) treating a compound of the formula: ##STR9## wherein R.sup.1, R.sup.2 and R.sup.3 are as defined above, with a base to cause migration of the double bond in order to obtain a compound of the formula: ##STR10## or
(e) reacting a compound of the following formula: ##STR11## wherein R.sup.1 and R.sup.2 are as defined above, with a compound of the formula R.sup.3 X wherein R.sup.3 is as defined above and X is halogen or an epoxide of formula ##STR12## wherein R.sup.5 is lower alkyl or hydroxyalkyl, whereupon the compound of Formula I is isolated as the free base or a pharmaceutically acceptable acid addition salt thereof and, in the case where one or two hydroxy groups are present, if desired, reacting the compound of Formula I with a reactive derivative of an aliphatic carboxylic acid having from 2 to 24 carbon atoms inclusive, and isolating the ester formed as the free base or an acid addition salt thereof.
The intermediates of Formula II, wherein X is hydroxy and Y is hydrogen, may conveniently be prepared according to the following scheme: ##STR13## wherein R.sup.1, R.sup.2 and R.sup.3 are as defined above.
The 3-phenylindanones (III) were synthesized according to methods well-known from the litterature.
Intermediates of Formula II, wherein X is hydrogen and Y is hydroxy, may conveniently be prepared from 3-pyridyl-indanones (IV) according to the following reaction scheme: ##STR14## of from 3-piperidylindanones according to the following scheme: ##STR15##
The substituents R.sup.1, R.sup.2 and R.sup.3 in these schemes are as defined above.
The 3-pyridylindanones (IV) and 3-piperidylindanones (V) were prepared according to methods described in the litterature (J. Med. Chem., 11, (1968), 1064-1066).
The dehydration of the compound II according to method variant (a) of the invention is conveniently carried out such as by hydrogen chloride or hydrogen bromide in an inert organic solvent, or by anhydrous trifluoroacetic acid. The reaction temperature is preferably kept low or near 50 degrees Centigrade.
The rearrangement according to method (b) may be carried out in aqueous media with strong mineral acids or strong alkalihydroxides, or by heating a salt in an organic solvent at a temperature of about 100 degrees Centigrade.
In method (c) the heating is preferably carried out in the presence of an inert solvent such as dimethyl-sulfoxide at about 100 degrees Centigrade.
In method (d) the migration of the double bond takes place in a strongly alkaline aqueous medium, such as sodium hydroxide solution.
The optional esterification of any hydroxy group or groups present in the compound of Formula I may, according to the invention, conveniently be carried out by a reactive derivative of the carboxylic acid having from two to twenty-four carbon atoms inclusive, such as an acid chloride or anhydride. As carboxylic acids may be mentioned acetic acid, propionic acid, valeric acid, decanoic acid, palmitic acid and behenic acid.